Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

Han, Feifei; Li, Liang; Shang, Bo-Yang; Shao, Rong‐Guang; Zhen, Yong‐Su

doi:10.7314/apjcp.2014.15.17.7043

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…Indeed, the impairment of Hsp90 function has been shown to enhance the cytotoxicity of a variety of chemical and physical DNA damaging agents ( i.e. , ionizing radiation (IR)), inhibiting, for instance, ATM-dependent repair mechanism [ 56 , 60 , 61 ]. In particular, the sensitivity of aneuploid cancer cells to Hsp90 inhibition seems to reflect the increased proteotoxic stress associated to the accumulation of misfolded proteins, as supported by the evidence that Hsp90 inhibition potentiates the effects of proteasome inhibitors in multiple myeloma [ 62 , 63 ].…”

Section: Hsp90 and Cancermentioning

confidence: 99%

Hsp90: A New Player in DNA Repair?

2015

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Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted.

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Section: Hsp90 and Cancermentioning

confidence: 99%

Hsp90: A New Player in DNA Repair?

2015

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“…Molecular chaperones are proteins which play a key role in the conformational maturation, stability and function of other "client" protein substrates within the cell. [3][4] Hsp90 is important for stabilization and trafficking of tyrosine and serine/threonine kinases that are activated in response to genotoxic stress, including those that are essential for survival of cancer cells Some Hsp90 inhibitors are currently in phase I/II clinical trials in combination with IR or chemotherapeutic agents [5][6][7] Here, in present study, we have performed the molecular docking study of ten derivatives of Bromo aniline molecules, such as 5a -5j against 4,5 Diaryl Isoxazole Hsp90 Chaperone (2VCJ) . [8]…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Bromo Aniline derivatives and an insilico approach against HSP90 chaperone

Meenakumari¹,

Girija²

2022

ijhs

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Heterocyclic compounds are occupied in a huge variety of drugs which are widely distributed in nature and essential to life; Aniline has its remarkable influence in products that have been used by humans in day to day life. Its derivatives have made a remarkable trend over drug synthesis and this work shows the synthesis, characterization of some Bromo aniline derivatives and their action against the insilico docking studies against 4,5 Diaryl Isoxazole Hsp90 Chaperone Inhibitors a potential skin cancer therapeutic agent (2VCJ).

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“…Among the Hsp90 clients identified, there are many proteins involved in DNA damage repair, such as DSBs repair MRN complex and SSBs (DNA single-strand break) repair CHK1. In addition, inhibition of Hsp90 can lead to DNA repair defects (such as homologous recombination repair [23,24]), enhance the cytotoxicity of DNA damaging agents [25][26][27], making cells more sensitive to DNA damage [28,29]. 17-AAG (Allylaminogeldanamycin), an inhibitor of Hsp90, has been used in clinical trials of breast cancer and other cancers [30].…”

Section: Introductionmentioning

confidence: 99%

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Wang

Chen

et al. 2021

Cell Death Dis

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Ovarian cancer is the most malignant gynecologic cancer. Previous studies found that lamin-A was associated with DNA damage repair proteins but the underlying mechanism remains unclear. We speculate that this may be related to its interacting proteins, such as Hsp90. The aim of this study is to investigate the effects of Hsp90 on DNA damage repair and chemoresistance of ovarian cancer cells. In our research, co-immunoprecipitation (co-IP) and mass spectrometry (MS) were used to identify proteins interacting with lamin-A and the interaction domain. Next, the relationship between lamin-A and Hsp90 was explored by Western blotting (WB) and immunofluorescence staining. Then, effect of Hsp90 inhibition on DNA damage repair was assessed through detecting Rad50 and Ku80 by WB. Furthermore, to test the roles of 17-AAG on cell chemosensitivity, CCK-8 and colony formation assay were carried out. Meanwhile, IC50 of cells were calculated, followed by immunofluorescence to detect DNA damage. At last, the mouse xenograft model was used in determining the capacity of 17-AAG and DDP to suppress tumor growth and metastatic potential. The results showed that lamin-A could interact with Hsp90 via the domain of lamin-A1-430. Besides, the distribution of Hsp90 could be affected by lamin-A. After lamin-A knockdown, Hsp90 decreased in the cytoplasm and increased in the nucleus, suggesting that the interaction between lamin-A and Hsp90 may be related to the nucleocytoplasmic transport of Hsp90. Moreover, inhibition of Hsp90 led to an obvious decrease in the expression of DSBs (DNA double-strand break) repair proteins, as well as cell proliferation ability upon DDP treatment and IC50 of DDP, causing more serious DNA damage. In addition, the combination of 17-AAG and DDP restrained the growth of ovarian cancer efficiently in vivo and prolonged the survival time of tumor-bearing mice.

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Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

Abstract: Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio-and chemo-therapy sensitivity.

Cited by 6 publications

References 25 publications

Hsp90: A New Player in DNA Repair?

Hsp90: A New Player in DNA Repair?

Synthesis of Bromo Aniline derivatives and an insilico approach against HSP90 chaperone

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

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